Malaria is a global health problem and causes 2 – 3 million deaths each year. Mosquito bites allow malaria parasites to enter the bloodstream. Within 30 minutes, the parasites are transported to the liver where they enter cells and start to reproduce rapidly. Following release from hepatocytes, the parasites re-enter the bloodstream and infect red blood cells, triggering the pathology that is associated with malaria.

The receptor on human liver cells that allows the malaria parasites to enter hepatocytes has been identified as the scavenger receptor (SR-B1). This receptor normally transfers cholesteryl esters and other lipids from high density lipoprotein (HDL) in the bloodstream into liver cells. A new study shows that, in cell culture experiments as well as experiments in mice, blocking the SR-B1 receptor dramatically reduced the ability of the malaria parasite to infect liver cells. The researchers used RNA interference (RNAi), monoclonal antibodies, and small molecule inhibitors to demonstrate the importance of the SR-B1 receptor for entry of malaria parasites into hepatocytes. The study demonstrates that blocking the SR-B1 receptor may offer a new approach to the prophylaxis of malaria.

Targeting host mechanisms promises better protection against the emergence of resistant strains of the malaria parasite but, in this case, should be balanced against the atherosclerotic potential of long term blockade of the SR-B1 receptor.

Bookmark It

Hide Sites

The journal Nature Chemical Biology defines chemical biology as ‘both the use of chemistry to advance a molecular understanding of biology and the harnessing of biology to advance chemistry’.

Scientists at the Karolinska Institute, Stockholm, have exploited the principles of chemical biology in the study of apoptotic pathways. In a recent publication, the scientists identified a set of 40 chemical agents (‘bioprobes’) that induce apoptosis from screening of a chemical library.

Using a variety of reporter cell lines, they were able to establish that the ‘bioprobes’ induced different patterns of signalling. Experiments using a calcium chelator, BAPTAAM, showed that Ca²⁺ was involved in induction of apoptosis by the majority of the ‘bioprobes’ and that Ca²⁺ was in general required several hours into the apoptosis process. Further studies showed that the calmodulin pathway was an important mediator of the apoptotic response. Inhibition of calmodulin kinase II (CaMKII) resulted in more effective inhibition of apoptosis compared to inhibition of calpain, calcineurin/PP2B or DAP kinase. One of the ‘bioprobes’, the plant alkaloid helenalin, was used to study the role of CaMKII in apoptosis. Helenalin induced CaMKII, ASK1 and Jun-N-terminal kinase (JNK) activity, and inhibition of these kinases inhibited apoptosis.

The study shows that calcium signalling is generally not an early event during the apoptosis process and suggests that a CaMKII/ASK1 signalling mechanism is important for sustained JNK activation and apoptosis by some types of stimuli.

Bookmark It

Hide Sites

The precise cause of psoriasis is not known but a number of factors, such as skin injury and infection, are thought to trigger outbreaks. T-cells become activated, leading to an acceleration of the normal replacement processes of the skin and an accumulation of skin cells as plaques on the surface of the skin. First line treatments include emollients and topical application of drugs such as vitamin D derivatives, coal tar preparations, steroids, vitamin A derivatives and dithranol. For refractory cases, retinoids or immunosuppressants may be prescribed. A recent study shows that the selective PKC inhibitor, AEB071, may become a new therapeutic option for the treatment of psoriasis. At a dose of 300 mg bid, AEB071 was well tolerated and improved the symptoms of psoriasis within a 2-week treatment period.

AEB071 is also undergoing clinical trials in kidney and liver transplant patients.

Bookmark It

Hide Sites

In the rare inherited human disease, ataxia-telangiectasia (A-T), a mutation is present in a gene encoding a protein that normally activates cellular responses to DNA damage. The mutation in the ATM gene leads to decreased ability to repair damaged DNA, and an increased sensitivity to ionising radiation and other DNA damaging agents. This highlights the ATM pathway as a potential target to increase the sensitivity of tumour cells to radiotherapy or chemotherapy. The ATM protein demonstrates kinase activity and a selective, small molecule inhibitor of this kinase, CP466722, has now been shown to enhance the sensitivity of tumour cells grown in vitro to ionising radiation.

Inhibition of ATM kinase activity is rapid, and is completely and rapidly reversed on wash-out; further experiments suggested that inhibition of ATM for a short period of time may be sufficient to sensitise tumour cell to radiotherapy. Because CP466722 is effective in murine cells as well as human cells, it may be possible to use mouse models to further explore the potential of using ATM inhibitors to increase the effectiveness of radiotherapy.

Bookmark It

Hide Sites

Multiple sclerosis (MS) is a disorder of the central nervous system with initial inflammation of the protective myelin sheath encasing nerve fibres. Symptoms vary widely and often occur initially as discrete episodes interspersed with relatively symptom-free periods (relapsing MS).

A drug currently being tested for its effectiveness in treating relapsing forms of MS is now to be tested to see whether it can prevent the disease from developing. The drug, cladribine, will be given orally to patients who have a first clinical event suggestive of MS. Patients will be treated for two years, or up to the time when they experience a second attack leading to a definite clinical diagnosis of MS. Treatment will be given in two or four cycles in the first year, with a single daily dose of cladribine tablets being given on four to five consecutive days in each cycle. This means that patients in the study will take cladribine for only 8 – 20 days in the first year. In the second year, two treatment cycles will be given to all patients.

Cladribine is also used as an intravenous infusion to treat hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphomas.

Bookmark It

Hide Sites

Migraine is very prevalent worldwide. Attacks are more common in women and can occur at any age, but often diminish after the age of 50. Migraine pain is usually described as a severe throbbing or pulsating headache, often with nausea and sensitivity to light, which can last for many hours or even days.

The benefits of Botulinum Toxin (Botox®) in migraine were discovered accidentally when injections to reduce lines and wrinkles were reported to reduce the frequency and severity of headaches. Top-line analyses of data from two Phase III clinic trials confirm that Botox® is effective for the prophylaxis of chronic migraine. Patients were given Boxtox® or placebo injections every 12 weeks, and the primary analysis was carried out after two treatment cycles. The efficacy measures were the change in number of headache episodes and headache days compared with the 28 days preceding treatment. One study showed no significant reduction in the number of headache episodes between patients receiving Botox® and placebo, but a significant reduction in the number of headache days in the treatment group. The second study showed a benefit in terms of both number of headache episodes and headache days for the Botox® treated group. In both studies, patients receiving Botox® treatment reported significantly improved quality of life compared with patients receiving placebo.

Bookmark It

Hide Sites

Type-2 diabetes is a metabolic disorder that is increasing rapidly in the developed world. The disease is caused by reduced production of insulin by the pancreas and /or reduced responsiveness to insulin by cells in the body, particularly fat, muscle and liver cells. Reduced insulin activity causes higher blood glucose levels as well as other complex metabolic changes, leading eventually to organ damage with increased morbidity and mortality.

A number of medicines are used to treat type-2 diabetes; these include metformin, sulphonyl ureas, and thiazolidinediones. More recently, inhibitors of dipeptidyl peptidase-4 (DPP-4) have emerged as an alternative method of treatment. DPP-4 inhibitors act by increasing levels of the gastrointestinal hormones, incretins, which increase the amount of insulin released by the pancreas, inhibit glucagon release and also slow gastric emptying.

New data has been presented showing that Januvia™ (sitagliptin), in combination with metformin, provided significant glucose lowering over two years. In separate studies, addition of Januvia™ to regimens based on thiazolidinediones also led to improved blood sugar control. Januvia™ was the first DPP-4 inhibitor to be approved for the treatment of diabetes in the US and Europe although several other inhibitors are in varying stages of development.

Bookmark It

Hide Sites

Protein folding is the process whereby newly synthesised linear polypeptide chains fold into the well-defined 3-dimensional shape of the functional protein. In many cases, molecular chaperones assist in correct protein folding by preventing the newly synthesised protein from aggregating into non-functional structures. A variety of diseases result from misfolded proteins; loss-of-function diseases are often caused by a point mutation in the sequence of the protein which disturbs the normal balance between protein folding and clearance. There has been recent interest in the development of ‘pharmacological chaperones’ which are small molecules that stabilise the correct protein fold.

A recent study describes two small molecules, celastrol and MG-132, that are able to enhance mutant protein folding and function in cell culture experiments. These compounds acted synergistically with known pharmacological chaperones and increased the activity of mutant proteins to 50% of wild-type activity. This study provides encouragement for the concept of developing regulators of proteostatis for the treatment of a range of loss-of-function diseases.

Bookmark It

Hide Sites

A new study describes a high affinity interaction between siramesine and phosphatidic acid, a component of cell membranes that also acts as a signalling molecule. Siramesine is a sigma receptor agonist, selective for the σ2 subtype, which was originally under development for the treatment of anxiety but failed to show efficacy in clinical trials.

Siramesine was subsequently shown to kill cancer cells by destabilising their lysosomes. Vincristine, a microtubule destabilising antimitotic drug, which is used in various chemotherapy regimens, greatly sensitised cancer cells to the cytotoxic effects of siramesine.

The new study suggests that it may be possible to design small molecules to specifically scavenge phospholipids involved in the signalling cascades controlling cell survival.

Bookmark It

Hide Sites

Prostate cancer is the most common cancer in men, with the majority of cases occurring in the over-65s. Rising levels of prostate specific antigen (PSA) are associated with both localized and metastatic prostate cancer and a blood test for PSA is used for the early detection of the disease.

A recent study suggests that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen may reduce measured serum PSA levels, although it was unclear whether this indicated a protective effect against prostate cancer or whether use of NSAIDs obscured the test results. Paracetamol, which has very little anti-inflammatory activity, did not show a statistically significant effect on serum PSA levels.

Earlier studies have suggested that aspirin may reduce the risk of metastatic prostate cancer but not the total risk of prostate cancer and that combined long-term use of statins and NSAIDs might be associated with a reduced risk of prostate cancer.

Since prostate cancer cells show unusually high levels of the enzyme COX-2, which is inhibited by NSAIDs, there is considerable interest in the potential for COX-2 inhibitors in the treatment of prostate cancer and several clinical studies have been initiated.

Bookmark It

Hide Sites